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<p>Herpes simplex virus 1 (HSV-1) is the most common cause of viral encephalitis, which can be lethal or result in severe neurological defects despite antiviral therapy. The apolipoprotein B messenger-RNA editing enzyme, catalytic polypeptide-like (APOBEC) group of proteins can act as viral restriction factors. How HSV-1 evades this intrinsic immune mechanism is unclear. Here, using human carcinoma HEp-2 cells, we find that phosphorylation and therefore activation of HSV-1 uracil-DNA glycosylase counteracts mouse APOBEC1 DNA-editing activity on HSV-1 genomes. This protects viral genomes, promotes viral replication and encephalitis in the central nervous system of mice. Presence of Apobec1 improved encephalitis outcomes in mice challenged with HSV-1 carrying a mutation in the phosphorylation site of uracil-DNA glycosylase. Treatment with an UNG inhibitor, adeno-associated virus vector expressing UGI, protected wild-type HSV-1-infected mice from lethal encephalitis. These findings identify uracil-DNA glycosylase as a viral factor enabling evasion from intrinsic antiviral immunity mediated by APOBEC1 in the central nervous system and suggests a potential therapeutic approach to treat HSV-1 encephalitis.</p>

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Herpes simplex virus 1 evades APOBEC1-mediated immunity via its uracil-DNA glycosylase in mice

  • 期刊论文

  • 发表日期：

    2025年6月3日

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  • Akihisa Kato,
  • Hayato Harima,
  • Yuji Tsunekawa,
  • Manabu Igarashi,
  • Kouichi Kitamura,
  • Kousho Wakae,
  • Tomoaki Nishiyama,
  • Satoru Morimoto,
  • Toru Suzuki,
  • Hiroko Kozuka-Hata,
  • Masaaki Oyama,
  • Daisuke Motooka,
  • Mizuki Watanabe,
  • Kousuke Takeshima,
  • Yuhei Maruzuru,
  • Naoto Koyanagi,
  • Hideyuki Okano,
  • Toshifumi Inada,
  • Takashi Okada,
  • Masamichi Muramatsu,
  • Yasushi Kawaguchi

摘要

Herpes simplex virus 1 (HSV-1) is the most common cause of viral encephalitis, which can be lethal or result in severe neurological defects despite antiviral therapy. The apolipoprotein B messenger-RNA editing enzyme, catalytic polypeptide-like (APOBEC) group of proteins can act as viral restriction factors. How HSV-1 evades this intrinsic immune mechanism is unclear. Here, using human carcinoma HEp-2 cells, we find that phosphorylation and therefore activation of HSV-1 uracil-DNA glycosylase counteracts mouse APOBEC1 DNA-editing activity on HSV-1 genomes. This protects viral genomes, promotes viral replication and encephalitis in the central nervous system of mice. Presence of Apobec1 improved encephalitis outcomes in mice challenged with HSV-1 carrying a mutation in the phosphorylation site of uracil-DNA glycosylase. Treatment with an UNG inhibitor, adeno-associated virus vector expressing UGI, protected wild-type HSV-1-infected mice from lethal encephalitis. These findings identify uracil-DNA glycosylase as a viral factor enabling evasion from intrinsic antiviral immunity mediated by APOBEC1 in the central nervous system and suggests a potential therapeutic approach to treat HSV-1 encephalitis.